Cells obtain energy from the oxidation of a variety of organic molecules, and oxygen is the primary oxidant in the biochemical reactions that perform this function. Oxidative stress, which results from the metabolic reactions that use oxygen, may be considered a disturbance in the equilibrium status of pro-oxidant/anti-oxidant systems in intact cells. Cells have intact pro-oxidant/anti-oxidant systems that continuously generate and detoxify oxidants during normal aerobic metabolism. When additional oxidative events take place, the pro-oxidant systems outbalance those of the anti-oxidant, which may result in oxidative damage to cell components including lipids, proteins, carbohydrates, and nucleic acids. Mild, chronic oxidative stress may alter the anti-oxidant systems by inducing or repressing proteins that participate in these systems, and by depleting cellular stores of anti-oxidant materials such as glutathione and Vitamin E. Severe oxidative stress may ultimately lead to cell death.
An imbalance in pro-oxidant/anti-oxidant systems may result from a number of different oxidative challenges, including radiation, metabolism of environmental pollutants and administered drugs, as well as immune system response to disease or infection. The immune response is of particular significance since many toxic oxidative materials are generated in order to attack invading organisms. A variety of chemicals called radicals have roles in these processes. A radical species is any atom that contains one or more orbital electrons with unpaired spin states. A radical may be a small gas molecule such as oxygen or nitric oxide, or it may be a part of a large biomolecule such as a protein, carbohydrate, lipid, or nucleic acid. Some radical species are very reactive with other biomolecules and others, like the normal triplet state of molecular oxygen, are relatively inert.
Of interest with respect to oxidative stress are the reactions of partially reduced oxygen products and radical and non-radical species derived from them. A variety of reactive nitrogen species derived from the reactions of nitric oxide also play important roles in oxidative stress.
Oxidative stress has been implicated in human and animal disease. Cells have, however, multiple protective mechanisms against oxidative stress that act in preventing cell damage. Many dietary constituents are important sources of protective agents including anti-oxidant vitamins and minerals as well as food additives that might enhance the action of natural anti-oxidants. The effectiveness of an anti-oxidant in oxidative stress may be dependent on the specific molecules causing the stress, and the cellular or extracellular location of the source of these molecules.
Intense exercise can contribute significantly to oxidative stress in a number of ways. Most individuals have at some time in their lives experienced soreness and fatigue after physical exertion. For animals that undergo intense, frequent exercising, the effects of oxidative stress can have negative effects on performance.
Intense exercise results in a number of physiological changes in the body. First, aerobic respiration is dramatically increased, thereby increasing superoxide anion generation as much as 10-fold or more (Halliwell, B. (1994) Free radicals and antioxidants: a personal view. Nutr. Rev. 52:253-265), in addition to increasing exposure to environmental oxidative insults such as air pollution. Second, muscle and joint inflammation often result from intense exercise, thus triggering tissue infiltration of neutrophils and subsequent release of reactive oxygen species during the “oxidative burst” characteristic of activated neutrophils mediated by the immune response.
Enhanced antioxidant intake in humans has been reported to decrease the risk of developing specific forms of cancer and to enhance immune function. The effects of dietary antioxidant intake on pathological and physiological processes such as the aging process and exercise in dogs have been reported in the scientific literature. The effects of enhanced intakes of Vitamins E and C on immune function, free radical formation and free radical scrubbers have also been reported.
Cataracts may develop due to metabolic disorders such as diabetes, and from exposure to light, followed by subsequent oxidation of the lens. Oxidative stress, therefore, directly contributes to cataract formation. Primary (diene conjugates, cetodienes) lipid peroxidation (LPO) products accumulate during the initial stages of cataract formation while LPO fluorescent end-products are dominant in the later stages (Babizhayev et al. (2004) Drugs R. D. 5(3):125-139). Lens opacity correlates with the LPO fluorescent end-product accumulation in the tissue, and decreased reduced glutathione leads to sulfhydryl group oxidation of lens proteins (Babizhayev et al. (2004) Drugs R. D. 5(3):125-139). It has been shown that direct injection of LPO products into the vitreous induces cataract formation (Babizhayev et al. (2004) Drugs R. D. 5(3):125-139). Thus, peroxide damage of lens fiber membranes appears to initiate the development of cataracts (Babizhayev et al. (2004) Drugs R. D. 5(3):125-139).
Osteoarthritis (OA) is also related to oxidative stress. Free radicals, including nitric oxide, superoxide anion and hydrogen peroxide, lead to upregulation of enzymes responsible for damage to articular cartilage. These enzymes (MMPs) are specific for collagen, elastin and gelatin.
Oxygen radicals with unpaired electrons are produced as a normal part of oxygen metabolism. These reactive molecules may cause damage to, for example, proteins, nucleic acids (i.e., DNA) and/or membranes which may result in serious cell injury and disease in the whole animal. This process has been associated with the aging process, degenerative diseases, and cancer.
Animals that may be particularly vulnerable to oxidative damage or stress include those that are very active. For instance, well-conditioned canine athletes are healthy animals, which by virtue of their tremendous rates of oxygen consumption generate more free radicals each day than their more sedentary counterparts. The changes in immune function, metabolic intermediates, tissue stores of antioxidants and antioxidant enzymes induced by free radical production are greater in canine athletes than sedentary animals.
Previous studies examining hard working dogs revealed that exercise was associated with a significant increase in plasma concentrations of isoprostanes, a stable by product of lipid peroxidation. These same studies also demonstrated a decrease in plasma Vitamin E concentrations during exercise. Further studies examined the effect of Vitamin E supplementation on these parameters. Vitamin E supplementation helped decrease or alleviate the exercise associated drop in plasma Vitamin E concentration but did not decrease the elevations in plasma isoprostanes.
Astaxanthin is a mixed carotenoid which may be found in a number of sources; it is present in high levels in algae. This pigment protects the algal organism from damage due to ultraviolet radiation exposure. Several studies have demonstrated immuno-stimulatory properties of astaxanthin in cultured cells as well as whole animals (mice). It is also used in sunscreen lotions as it has been demonstrated to diminish reddening of the skin after sun exposure. Astaxanthin supplementation has also been associated with increased endurance in untrained human subjects.